Polymeric drug formulations

ABSTRACT

Polymeric drug formulations containing a non-releasing single-phase dispersion of a water-soluble drug in a water-insoluble tissue-compatible polymer matrix. Polymeric drug formulations are also disclosed containing a single-phase dispersion of a water-soluble drug and a water-insoluble tissue-compatible polymer matrix, and a second, phase-disrupting polymer that is non-miscible with the tissue-compatible polymer and is present in an amount sufficient to form phase-separated microdomains of the second polymer in the tissue-compatible polymer matrix, so that the release rate of the water-soluble drug from the tissue-compatible polymer matrix is related to the amount of the second polymer. Methods of preparing the polymeric drug formulations are also described, as well as methods for site-specific drug delivery utilizing the polymeric drug formulations.

BACKGROUND OF THE INVENTION

The present invention relates to polymeric drug formulations in the formof solid single-phase dispersions of water-soluble drugs inwater-insoluble tissue-compatible polymer matrices. The presentinvention additionally relates to solid single-phase dispersions ofwater-soluble drugs in water-insoluble tissue-compatible polymermatrices that include a second, phase-disrupting polymer so thatphase-separated microdomains form in the matrices, which results in therelease rate of the drug from the polymer matrix being affected by theamount of the second polymer present.

The present invention also relates to methods for forming the polymericdrug formulations of the present invention in which the water-solubledrug, the water-insoluble tissue-compatible polymer and, optionally, thesecond phase-disrupting polymer are dissolved in a common solvent andthen coprecipitated by the addition to the solution of a carefullyselected non-solvent. The resulting coprecipitate is in the form of asolid single-phase dispersion of the drug and polymer with the secondpolymer, when present, being concentrated in phase-separatedmicrodomains. The present invention also relates to methods forsite-specific drug delivery by implanting in the body of a patient inneed thereof the polymeric drug formulations of the present invention.

In the context of this invention, a water-soluble drug is defined as ahydrophilic compound with a solubility in water greater than 1 percent(w/v) and that is practically insoluble in nonpolar organic solventssuch as ethyl acetate, methylene chloride, chloroform, toluene, orhydrocarbons. Peptide-based drugs represent a particularly importantclass of water-soluble drugs as defined here.

When such water-soluble drugs are incorporated into polymers, it isoften difficult to prevent the rapid, uncontrolled release of drug in aburst-like fashion from the drug-polymer matrix. This is known as the"burst effect". The burst effect becomes particularly noticeable at highdrug loadings. Within the context of this invention, high levels of drugloading are defined as drug loadings in excess of 10 percent (w/w) basedon the weight of drug contained per 100 mg of drug-polymer matrix. Theterm "lag effect" refers to the phenomenon that the rate of drug releasefrom a drug-polymer matrix decreases to zero or close to zero, e.g., therelease of drug stops for a certain period of time. Burst effects andlag effects are some of the commonly observed phenomena that renderdrug-polymer matrices unsuitable as "controlled release systems" forclinical applications.

The physical state of the drug-polymer mixture, also referred to as themorphology of the system, is an often overlooked key parameter in thedesign of polymeric drug delivery systems. In the context of the presentinvention, one can distinguish between the following fundamentallydifferent morphological states: single-phase dispersions and multi-phasedispersions.

In single-phase dispersions the drug is dispersed within the polymericphase on a molecular scale. Within the context of this invention, asingle-phase dispersion is defined as a drug-polymer matrix that appearstransparent and clear to transmitted visible light. This simplerequirement indicates that the drug-polymer matrix is free ofmicrodomains on the length-scale of visible light and therefore does notscatter transmitted visible light. The formation of a single-phasedispersion requires not only that the drug and polymer have some mutualmiscibility, but requires also a method for creating a moleculardispersion of the drug within the polymeric phase. This is an important,often overlooked point: If a drug and polymer particles are simply mixedwithout creating a molecular dispersion of the drug in the polymermatrix, a single-phase dispersion cannot form, even if drug and polymerare mutually miscible.

In multi-phase dispersions, phase-separated domains exist within thedrug-polymer matrix. In multi-phase dispersions, microdomains havingdimensions on the length scale of visible light may be present. Withinthe context of the present invention, such dispersions are readilydiscerned by the property that the drug-polymer matrices are translucentto visible light, but appear hazy, cloudy, or foggy. Alternatively, thedrug may be present in the form of distinct particles or crystalsreadily discernible by microscopic examination of the drug-polymermatrix. In the extreme case, the drug may be embedded within the polymerin the form of macroscopic particles, readily visible upon inspection bythe naked eye.

Hydrophobic polymer matrices of both degradable and nondegradablepolymers have been studied as potential vehicles for drug delivery.Although this invention is applicable to both degradable andnondegradable polymers, the following discussion is focused on the morecomplex degradable systems since the theory of drug release fromnondegradable systems is well-known to those skilled in the art. Inaddition, degradable drug release formulations are generally recognizedas particularly useful as implants for the delivery of peptide drugs,which, because of their low oral bioavailabilities and short half-livesin plasma, cannot be administered by conventional oral and parenteralroutes.

Release characteristics from degradable polymer matrices are influencedby several factors, the most important factors being drug loading, thephysical state of the drug within the polymeric matrix, and the rate ofpolymer degradation and erosion as determined by the composition,morphology, and molecular structure of the polymeric matrix.

Drug loading affects the release mechanism and release rate. In theprior art, the simple case of a multi-phase dispersion in which drugparticles are dispersed within the polymeric phase is well understood.Briefly, at low loadings, individual drug particles have no contactbetween each other. Water and/or drug molecules must diffuse through thepolymer matrix to allow drug release, which consequently leads to slowrelease. Drug particles entrapped within the polymeric matrix may not bereleased at all until polymer degradation leads to the physical erosionof the polymeric matrix. At high loadings, individual drug particles arein physical contact with each other and the dissolution of individualparticles results in the formation of discrete pores within thepolymeric matrix through which drug is released by slow diffusion (seeSiegel and Langer, J. Control. Rel., 14, 153-67 (1990)).

Often, the effect of drug loading is much more complex since the loadinglevel will influence the morphology of the drug-polymer matrix. Thispoint is often overlooked in the prior art. If a drug is only partiallymiscible with the polymer, a single-phase dispersion may be formed atlow loadings. However, as the loading level is raised above the limitedmiscibility between the drug and the polymer, multi-phase dispersionsare formed. At this point, a dramatic difference in the releasemechanism is usually observed. The release rates and mechanisms areparticularly difficult to analyze in formulations in which some fractionof the drug forms a single-phase blend with the polymeric matrix, whileanother fraction is present in the form of phase-separated domains.

In the prior art it is well-known that control of particle size andhomogeneity of the drug dispersion within the polymeric phase iscritical in order to obtain reproducible and prolonged drug releaseprofiles. The formulation of polymeric drug delivery devices forwater-soluble drugs as defined above is especially challenging becauseit is difficult to obtain uniformly dispersed mixtures of such drugswithin a water-insoluble polymeric phase. This is due to the fact thatno single solvents are available capable of dissolving the water-solubledrug and the water-insoluble polymeric matrix simultaneously to form ahomogeneous solution from which a uniformly dispersed mixture of drugand polymer may be readily recovered. For that reason, particles of awater-soluble drug are often suspended within a solution of the polymerin an organic solvent such as methylene chloride. Upon solvent casting,the discrete drug particles are embedded within the polymeric phase in amulti-phase dispersion where the exact distribution of the drugparticles is difficult to control and difficult to reproduce. Thistechnique cannot lead to the molecular dispersion of the drug within thepolymeric matrix. Alternative techniques for the formulation ofpolymeric controlled release devices for water-soluble drugs require thesimultaneous co-extrusion or co-molding of drug particles mixed withpolymer particles. Such processes are known in the literature but havesignificant limitations, namely, the methods are only applicable todrug-polymer combinations that can be thermally processed below thedecomposition temperature of the drug. In addition, these techniquesresult in the aggregation of drug and polymer in discrete domains thatresult often in undesirable release profiles.

In some cases, careful physical admixture can produce formulationshaving acceptable release profiles. However, such formulations haverelease profiles that are complex functions of drug loading levels, sizeand distribution of drug particles within the polymeric matrix, and therate of polymer degradation. For example, instead of extending theduration of drug release, elevated drug loadings usually lead tosignificant burst effects and an increase in the rate of drug release.Thus, it is difficult to design a suitable formulation providing animmediate release of drug at a reproducible and acceptable rate, withoutburst or lag effects with sustained release over extended periods oftime. This is but one example of the design limitations inherent inpolymeric drug delivery systems in which the rate of drug release isdetermined by drug loading, particle size and distribution, and/orpolymer degradation.

Sturesson et al., Intern. J. Pharm., 89, 235-44 (1993), addedpoly(ethylene glycol) (PEG) to a poly(lactic acid-co-glycolic acid)matrix to enhance the drug release rate by providing a system with agreater content of water-soluble substances in the polymer matrix,expecting the material to facilitate polymer hydrolysis and promotediffusional release of the water-soluble drug in the matrix. However, anenhanced rate of drug release was not observed.

A means by which the effects of particle size and distribution on therelease profile can be minimized and by which drug release from apolymeric matrix may be controlled independent of drug loading orpolymer degradation would be highly desirable.

SUMMARY OF THE INVENTION

This need is met by the present invention. It has now been discoveredthat the drug release rate from single-phase dispersions ofwater-soluble drugs in water-insoluble tissue-compatible polymermatrices may be controlled by including a second polymer in thetissue-compatible polymer matrix that is non-miscible with the basicpolymer matrix, so that phase-separated microdomains of the secondpolymer are formed in the drug-polymer matrix.

While not being bound by any particular theory, it is believed that thephase-separated microdomains disrupt the monolithic or homogeneous phaseof the single-phase drug-polymer dispersion such that the release rateof the drug from the polymer matrix is related to the amount ofphase-disrupting second polymer present. The present inventionrepresents a means by which the drug release profile from a polymermatrix may be modified and fine-tuned independent of the level of drugloading, the drug particle size, the distribution of drug particleswithin the polymeric matrix, or the degradation rate of thetissue-compatible polymer.

The single-phase dispersions of the present invention of water-solubledrugs in water-insoluble tissue-compatible polymer matrices have theunexpected and surprising property that the drug is not released fromthe drug-polymer matrix to any appreciable extent, even at highloadings. This property is not anticipated by the teachings in the priorart according to which the incorporation of high loadings of awater-soluble drug should have resulted in the observation of a strongburst effect, swelling (due to water-uptake by the drug-polymer matrix),and the rapid release of most of the drug in contact with the matrixsurface. Instead, in the single-phase dispersions of the presentinvention, drug release occurs only if a second phase-disrupting polymeris added into the formulation.

In the absence of such a phase-disrupting, second polymer, in mostinstances, the drug will be expressed at the matrix surface withoutbeing actually released from the polymeric matrix to any appreciableextent. Such a non-releasing formulation could be useful for sometherapeutic applications of water-soluble drugs where the drug iseffective as a surface modifying agent. Therefore, according to oneaspect of the present invention, a polymeric drug formulation isprovided that is a non-releasing single-phase dispersion of awater-soluble drug in a water-insoluble tissue-compatible polymermatrix.

The single-phase dispersions of the present invention are formed bysimultaneously dissolving the drug and matrix polymer in an organicsolvent system in which the drug and polymer are capable of forming ahomogeneous solution. The homogeneous solution of drug and polymer canbe used directly for the fabrication of coatings, tubes, filaments orfilms by appropriate fabrication techniques. Alternatively, thehomogeneous solution can be precipitated into a carefully selectednon-solvent, resulting in the formation of an intimate, molecularlydispersed co-precipitate of drug and polymer.

Therefore, another aspect of the present invention includes a method offorming a single-phase dispersion of a water-soluble drug with awater-insoluble tissue-compatible polymer. This requires that the drugis miscible in the solid phase with the polymer, and that a solventsystem can be identified that is capable of forming a homogeneoussolution of the drug and polymer, followed by the addition to thehomogeneous solution of a carefully selected non-solvent for the drugand polymer so that the drug and polymer coprecipitate from the solutionas a solid single-phase dispersion of the drug and polymer. This aspectof the present invention also includes polymeric drug formulationsprepared by this method of the invention.

The inclusion of a second phase-disrupting polymer to the drug-polymermatrix to control the drug release profile provides a polymer drugformulation useful in the therapeutic applications of water-solubledrugs in general and peptide-based drugs in particular. Therefore, yetanother aspect of the present invention provides a polymeric drugformulation that is a single-phase dispersion of a water-soluble drug ina water-insoluble tissue-compatible polymer matrix, which includes asecond, phase-disrupting polymer that is non-miscible with thetissue-compatible polymer and is present in an amount sufficient to formphase-separated microdomains of the second polymer in thetissue-compatible polymer matrix, so that the release rate of thewater-soluble drug from the tissue-compatible polymer matrix is relatedto the amount of the second polymer.

The polymeric drug formulations of the present invention containing asecond phase-disrupting polymer are likewise formed by dissolving thetissue-compatible polymer, drug and second phase-disrupting polymer in asolvent system capable of forming a homogeneous solution of all threecomponents. The homogeneous solution can also be directly fabricated toprovide coatings, tubes, filaments, films, microspheres or other shapedarticles, by appropriate fabrication techniques, or precipitated into anon-solvent to form an intimate, molecularly dispersed mixture of thedrug, tissue-compatible polymer, and the second phase-disrupting polymercontaining phase-separated microdomains having dimensions on the lengthscale of the wavelength of visible light.

Therefore, another aspect of the present invention provides a method offorming a polymeric drug formulation by blending a water-soluble drugwith a water-insoluble tissue-compatible polymer and a second,phase-disrupting polymer, that is non-miscible with the drug-deliverypolymer, in a solvent system capable of forming a homogeneous solutionof the drug, the polymer and the second, phase-disrupting polymer, andadding to the solution an amount of a non-solvent for the drug, thetissue-compatible polymer and the second, phase-disrupting polymer, sothat a microdomain-separated solid coprecipitate of the drug, thetissue-compatible polymer and the second, phase-disrupting polymer isformed, wherein the second, phase-disrupting polymer is blended in anamount effective to form separated microdomains. This aspect of thepresent invention likewise includes polymeric drug formulations preparedby this method of the invention.

The polymeric drug formulations of the present invention are intendedfor use as medical implants. Therefore, still yet another aspect of thepresent invention provides a method for site-specific drug delivery byimplanting in the body of a patient in need thereof the polymeric drugformulations of the present invention.

The polymeric drug formulations of the present invention areparticularly useful when formulated with platelet aggregation inhibitingpeptide drugs to improve the clinical performance of stents, the smallmetal springs used to prevent injured arteries from collapsing during orafter angioplasty or other cardiovascular procedures. Typically, stentsare placed into an artery, but the metal surface will often result inblood clotting at the stent surface and lead to occlusion of the artery.When the polymeric drug formulations of the present invention are loadedwith platelet aggregation inhibiting peptide drugs and placed in-betweenthe arterial wall and the stent, the local release of the plateletaggregation inhibiting peptide drug will reduce the tendency of blood toform clots at the implant site.

The present invention can be used to prepare polymeric films containingup to 30 percent by weight of a platelet aggregation inhibiting peptidedrug. The films are pliable, deformable, soft, elastic and translucent,yet are mechanically strong enough to withstand pulling and deformationduring handling. Depending on the exact formulation and amount of thephase-disrupting second polymer added into the formulation, the filmswill release biologically active and chemically pure plateletaggregation inhibiting peptide drugs for periods ranging from severalhours to several weeks. The mechanical and release properties of filmsof the polymeric drug formulations of the present invention containingplatelet aggregation inhibiting peptide drugs are ideally suited forplacement around an intra-arterial stent.

Methods for site-specific drug delivery in accordance with the presentinvention therefore include implanting the polymeric drug formulation ofthe present invention containing a platelet aggregation inhibitingpeptide drug during or following a cardiovascular procedure in which astent is inserted into an artery, by placing a film of the drugformulation between the arterial wall and the stent, so that localrelease of the platelet aggregation inhibiting peptide drug will reducethe formation of blood clots at the stent insertion site.

Polymeric drug formulations according to the present inventioncontaining platelet aggregation inhibiting peptide drugs are also usefulin the formulation of a wider range of medical devices and implants thatcome in contact with blood. Whenever a blood-contacting device is usedfor any length of time, the patient has to undergo anticoagulationtherapy to prevent the formation of blood clots at the device surface.The acute thrombogenicity of artificial surfaces can be reduced by therelease of a platelet aggregation inhibiting peptide drug from thedevice surface. Therefore, the polymeric drug formulations of thepresent invention containing an anti-thrombotic peptide drug can be usedto form coatings on existing device surfaces by dipping or spray-coatingtechniques. Specific applications include the reformulation of thesurface of vascular grafts, the formulation of new blood bags, and thereduction of the thrombogenic potential of tubings and membranes thatcome in contact with blood in extracorporeal devices.

Therefore, methods for site-specific drug delivery in accordance withthe present invention will also include implanting in the body of apatient a blood-contacting device or implant coated with the polymericdrug formulation of the present invention in which the drug is aplatelet aggregation inhibiting peptide drug. The present inventiontherefore also includes blood-contacting devices or implants coated withthe polymeric drug formulation of the present invention in which thedrug is a platelet aggregation inhibiting peptide drug.

A more complete appreciation of the invention and many more otherintended advantages can be readily obtained by reference to thefollowing detailed description of the preferred embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The polymeric drug formulations of the present invention are based onwell-known tissue-compatible polymers. Depending upon the intendedend-use, the tissue-compatible polymer may be degradable ornon-degradable under physiological conditions. The polymer to be used inthis invention has to be readily soluble in a wide range of solvents andchemically compatible with the drug to be delivered. Suitable candidatematerials for use in this invention are the previously-describeddegradable poly(carbonates) disclosed by U.S. Pat. No. 5,099,060, thepoly(iminocarbonates) described by U.S. Pat. No. 4,980,449 and thepoly(arylates) disclosed by U.S. Pat. No. 5,216,115. The disclosures ofall three patents are incorporated herein by reference. The tyrosinedipeptide-derived poly(carbonates), poly(iminocarbonates) andpoly(arylates) disclosed therein are preferred, with tyrosinedipeptide-derived poly(arylates) being particularly preferred. The mostpreferred tyrosine dipeptide derived poly(arylate) ispoly(desaminotyrosyl-tyrosine hexyl ester adipate) (poly(DTH adipate)).Poly(DTH adipate) having a weight-average molecular weight rangingbetween about 80,000 and about 200,000 daltons is particularlypreferred.

Other well-known tissue-compatible polymers that may be used includepoly(lactic acid), poly(glycolic acid), and co-polymers thereof,poly(ethylene-co-vinyl acetate), (commonly referred to by itsabbreviation EVA), poly(caprolactone), poly(orthoesters),poly(vinylpyrrolidone), pyran copolymer,poly(hydroxypropyl-methacrylamide-phenol),poly(hydroxyethyl-aspartamide-phenol), poly(ethylene oxide)-poly(lysine)substituted with palmitoyl residues, poly(hydroxybutyric acid),poly(acetals), poly(dihydropyran), poly(cyanoacrylates) and cross-linkedand amphipathic block copolymers of hydrogels, and the like. The polymermolecular weight will depend upon the requirements of the intended enduse of the polymeric drug formulation. The polymer molecular weight isone factor to be considered for drug compatibility and an appropriatepolymer molecular weight can be readily determined by one of ordinaryskill in the art without undue experimentation.

In addition to being chemically compatible with the tissue-compatiblepolymer, drugs for use in the polymeric drug formulations of the presentinvention must possess at least some solubility in the non-aqueoussolvent systems of the present invention and must be chemically stablein the solvent systems. While the polymeric drug formulations areparticularly well-suited for the delivery of peptide drugs, non-peptidedrugs may be used as well. Examples of suitable non-peptide drugsinclude natural and unnatural antibiotics, cytotoxic agents, andoligonucleotides.

The polymeric drug formulations in the present invention areparticularly well-suited for the delivery of peptide drugs and overcomesome of the difficulties encountered in previous attempts to formulatecontrolled release devices that show reproducible release profileswithout burst and/or lag effects, and the premature deactivation of thedrug during fabrication of the device. The peptide drugs suitable forformulation with the compositions of the present invention includenatural and unnatural peptides, oligopeptides, cyclic peptides, librarygenerated oligopeptides, polypeptides, and proteins, as well as peptidemimetics and partly-peptides, as long as the specific drug moiety hassome solubility in a single solvent or solvent mixture such that thedrug moiety and the water-insoluble polymer can form a homogenoussolution. The peptide drugs may be obtained by some form of chemicalsynthesis or be naturally produced or be obtained by recombinantgenetics, and can range in molecular weight as low as 200 daltons.

Suitable peptide drugs include immunoglobulins and immunoglobulinfragments. Peptide drugs of particular interest include plateletaggregation inhibiting peptides, which are antagonists of the cellsurface glycoprotein IIb/IIIa, thus preventing platelet aggregation andultimately clot formation. Preferred platelet aggregation inhibiting(PAI) peptides include the PAI peptides disclosed by published PCTApplication No. WO 90/15620, the disclosure of which is incorporatedherein by reference.

The following PAI peptides are particularly preferred:

PAI 1:E-C-A-D-G-L-C-C-D-Q-C-R-F-L-K-K-G-T-V-C-R-V-A-K-G-D-W-N-D-D-T-C-T-G-Q-S-C-D-C-P-R-N-G-L-Y-G

PAI 2:E-E-P-C-A-T-G-P-C-C-R-R-C-K-F-K-R-A-G-K-V-C-R-V-A-K-G-D-W-N-N-D-Y-C-T-G-K-S-C-D-C-P-R-N-P-W-N-G

PAI 3: G-C-G-K-G-D-W-P-C-A-NH₂

PAI 4: G-C-K-G-D-W-P-C-A-NH₂

PAI 5: C-G-K-G-D-W-P-C-NH₂

PAI 7: C-K-G-D-W-C-A-NH₂

PAI 9: Mpr-K-G-D-Pen-NH₂

PAI 10: C-K-G-D-W-P-C-NH₂

PAI 12: C-K-G-D-W-P-C-NH₂

PAI 13: C-K-G-D-F-P-C-NH₂

PAI 14: C-K-G-D-L-P-C-NH₂

PAI 15: C-K-G-D-V-P-C-NH₂

PAI 16: C-K-G-D-Y(OMe)-P-C-NH₂

PAI 17: C-K-G-D-(2-Nal)-P-C-NH₂

PAI 18: C-K-G-D-(Cha)-P-C-NH₂

PAI 19: Mpr-K-G-D-W-P-C-NH₂

PAI 20: Mpr-K-G-D-Y-P-C-NH₂

PAI 21: Mpr-K-G-D-F-P-C-NH₂

PAI 22: Mpr-K-G-D-L-P-C-NH₂

PAI 23: Mpr-K-G-D-V-P-C-NH₂

PAI 24: Mpr-K-G-D-Y(OMe)-P-C-NH₂

PAI 25: Mpr-K-G-D-(2-Nal)-P-C-NH₂

PAI 26: Mpr-K-G-D-(Cha)-P-C-NH₂

PAI 27: cyclo(G-K-G-D-W-P)

PAI 28: cyclo(A-K-G-D-W-P)

PAI 29: cyclo(A.sup.† -K-G-D-W-P)

PAI 30: cyclo(F-K-G-D-W-P)

PAI 31: cyclo(beta-Ala-K-G-D-W-P)

PAI 32: cyclo(gamma-Abu-K-G-D-W-P)

PAI 33: cyclo(R-K-G-D-W-P)

PAI 34: C-K-G-D-W-G-C-NH₂

PAI 37: C-K-A-D-W-P-C-NH₂

PAI 39: C-K-G-D-W-(Sar)-C-NH₂

PAI 41: C-K-G-D-I-P-C-NH₂

PAI 42: C-K-G-D-(4-Cl-Phe)-P-NH₂

PAI 43: C-K-(Sar)-D-W-P-C-NH₂

PAI 44: C-K-G-D-(4-NO₂ -Phe)-P-C-NH₂

PAI 47: Acetyl-C-K-G-D-W-P-C-NH₂

PAI 48: Mpr-K-G-D-W(Formyl)-P-C-NH₂

PAI 49: Mvl-K-G-D-W-P-C-NH₂

PAI 51: Mpr-K-G-D-W-P-Pen-NH₂

PAI 52: Mpr-K-G-D-W-P-Pen.sup.† -NH₂

PAI 54: Mpr-K-G-D.sup.† -W-P-Pen-NH₂

PAI 55: Mpr-K-G-D-W-(Thz)-C-NH₂

PAI 56: Mpr-K-G-D-H(2,4-DNP)-P-C-NH₂

PAI 57: Mpr-K-G-D-(2-Nai)-P-Pen-NH₂

PAI 58: Mvl-K-G-D-W-P-Pen-NH₂

PAI 59: Mpr-K-G-D-W-(Pip)-Pen-NH₂

PAI 60: Mpr-(Har)-G-D-W-P-C-NH₂

PAI 61: Mpr-K-G-D-W-P-C.sup.† -NH₂

PAI 62: Mpr-K.sup.† -G-D-W-P-Pen-NH₂

PAI 63: Mpr-(Har)-G-D-W-P-Pen-NH₂

PAI 64: Mpr-(Acetimidyl-Lys)-G-D-W-P-C-NH₂

PAI 65: Mpr-(Acetimidyl-Lys)-G-D-W-P-Pen-NH₂

PAI 66: Mpr (N^(G),N^(G') -ethylene-Har)-G-D-W-P-C-NH₂

PAI 67: Mpr (N^(G),N^(G') -ethylene-Har)-G-D-W-P-Pen-NH₂

PAI 68: Mpr-Har-Sar-D-W-P-C-NH₂

PAI 69: Mpr-(Acetimidyl-Lys)-G-D-W-P-Pen-NH₂

PAI 70: Mpr-(Phenylimidyl-Lys)-G-D-W-P-C-NH₂

PAI 71: Mpr-Har-Sar-D-W-P-PenNH₂

PAI 72: Mpr-(Phenylimidyl-Lys)-G-D-W-P-PenNH₂

PAI 73: Mpr-Har-G-D-W-(3,4-dehydro-Pro)-C-NH₂

PAI 74: Mpr-Har-G-D-Pen-NH₂

PAI 75: Mpr-(Phenylimidyl-Lys)-G-D-Pen-NH₂

PAI peptides are chemically compatible with poly(DTH adipate) disclosedby U.S. Pat. No. 5,216,115. Pliable, deformable, soft, elastic andtransparent films of poly(DTH adipate) containing up to 30 percent byweight of PAI peptides can be produced according to the methods of thepresent invention.

The chemical compatibility of drugs with tissue-compatible polymers canbe readily determined by one of ordinary skill in the art without undueexperimentation. Methods to evaluate chemical compatibility between thepolymer and a drug moiety have been described for the case ofpolyanhydrides by K. W. Leong, P. D. Amore, M. Marlett, and R. Langer,J. Biomed. Mater. Res., 20, 51-64 (1986). These methods are generallyapplicable and involve the fabrication of drug-loaded polymeric matricesby several techniques, followed by the evaluation of polymer molecularweight, drug purity, and the identification of any newly formed chemicalspecies by HPLC, FT-IR or other analytical techniques.

An important issue is the evaluation of mutual miscibility between thepolymer and the drug. According to the present invention, the drugmoiety and the polymeric matrix must be miscible (blendable) in thesolid state. The theoretical criteria (as well-known to anyone skilledin the art-see Billmeyer, Textbook of Polymer Science) for miscibilityis a shift in the polymer glass transition temperature upon mixing ofthe drug with the polymer. An empirical criteria, as defined here withinthe context of this invention, is that upon solvent casting, extrusion,or compression molding a mixture of polymer and drug, a transparentdevice is obtained that is free of discrete drug particles visible tothe naked eye. Transparency of the device indicates that the drug loadedpolymeric matrix does not contain phase separated microdomains on thelength scale of visible light, while a translucent device having a fogy,cloudy, or hazy appearance can be assumed to contain phase-separatedmicrodomains on the length scale of visible light.

The polymer drug formulations of the present invention may contain drugloadings from trace levels to about 50 percent by weight. Higher drugloadings will be useful only in rare circumstances. Preferably, thecompositions contain a therapeutically effective amount of the drug.Drug loading levels of about 30 percent by weight may be employedwithout detracting from the mechanical properties of films and coatingsformed from the compositions of the present invention. Most preferredembodiments are expected to have drug loadings from about 10 to 20percent by weight.

The polymeric drug formulations of the present invention may optionallyinclude a second, phase-disrupting polymer that is non-miscible with thetissue-compatible polymer. The term "non-miscible" is used in itsordinary sense with respect to the two polymers as defined by Billmeyer,Textbook of Polymer Science (3rd Ed., John Wyley & Sons, 1984).

One of ordinary skill in the art can easily select a second,phase-disrupting polymer that is non-miscible with a tissue-compatiblepolymer without undue experimentation. As a general rule, since thetissue compatible matrix polymer is water-insoluble, water-solublepolymers are good candidates for use as phase-disrupting polymers sincethese materials will usually be non-miscible with the matrix polymer.Water-solubility is additionally expected to be a favorable property forthe phase disrupting polymer since it can enhance the observed releaserate of the drug from the drug-polymer matrix. Examples of suitablenon-miscible polymers include poly(alkylene oxides) such aspoly(ethylene glycol) (abbreviated: PEG), polysaccharides, poly(vinylalcohol), polypyrrolidone, poly(acrylic acid) and its many water-solublederivative such as poly(hydroxyethyl-methacrylate), and the like. Thepresent invention also contemplates the use of non-polymeric materialsthat are non-miscible with the tissue-compatible polymer and result inthe formation of phase-separated microdomains.

As a general rule, the exact molecular weight of the phase-disruptingpolymer is not a critical parameter and needs to be determined on atrial and error basis, using phase-disrupting polymer preparations ofdifferent molecular weights and observing the resulting releaseprofiles. However, this can be performed by one of ordinary skill in theart without undue experimentation.

Molecular weights in the range of about 1,000 daltons to several hundredthousand daltons are useful. One of ordinary skill in the art candetermine the optimal molecular weight of the phase -disrupting polymerneeded to obtain the required release profile suitable for any givenmedical application. PEG is particularly well suited for use incombination with poly(DTH adipate) and PAI peptide. PEG having aweight-average molecular weight ranging between about 1,000 and about2,000 daltons is particularly preferred. When PEG is used as the secondphase-disrupting polymer, it should be present at a level between about2 and about 30 percent by weight. A level between about 5 and about 15percent by weight is preferred, with a level of about 10 percent byweight being most preferred.

As the concentration of the second, phase-disrupting polymer increasesin the formulation, the rate of drug release from the polymer matrixwill also increase, although this relationship is not linear. The drugrelease rate selected will depend upon the therapeutic dosage profilerequired for the drug to be delivered. However, this also can be readilydetermined by one of ordinary skill in the art without undueexperimentation.

The polymeric drug formulations of the present invention are prepared bysimultaneously dissolving the tissue-compatible polymer, drug andoptional second, phase-disrupting polymer in an organic solvent systemcapable of forming a homogenous solution of the tissue-compatiblepolymer, drug and second polymer, if present. Typical solvent systemswill include one or more solvents selected from methanol, methylenechloride, ethanol, ethylene glycol, glycerol, tetrahydrofuran, ethylacetate, acetonitrile, acetone, diisopropyl ether, methyl t-butyl ether,chloroform, carbon tetrachloride, dichloroethane, and water. Individualdrug and polymer components must possess a solubility in at least one ofthe solvents of at least 1 g/l. The solvents may be pre-blended beforethe drug and the polymer(s) are dissolved therein. Alternatively, drugor polymer may be dissolved in the individual solvent in which it ismost soluble, after which the solutions are combined to form a solventsystem in which the drug and polymer(s) are dissolved.

The drug and polymer(s) should be dissolved in the mixing solvents at alevel preferably between about 1 and about 30 percent by weight, andpreferably between about 5 and about 20 percent by weight. Aconcentration between about 5 and about 10 percent by weight is mostpreferred.

The relative solubilities of the drugs and polymers intended for usewith the present invention in various organic solvents are well-knownchemical properties. The selection of an organic solvent system in whicha drug, a tissue-compatible polymer and optionally a second,phase-disrupting polymer are forming a homogeneous solution at theirrespective concentrations may be readily determined without undueexperimentation.

Briefly, using the known solubility profiles of each individualcomponent, one would first consider a simple mixture of each of theindividual solvents. For example, if the drug has some solubility inacetone, the phase-disrupting polymer is soluble in methanol, and thetissue compatible polymer is soluble in methylene chloride, a mixture ofacetone, methanol, and methylene chloride would be the initial startingpoint for the development of a solvent system that can dissolve allthree of the components in a homogenous solution. Next, hydrogen bondingeffects, polarity effects, and common solvent effects are considered.Inspection of the well-known solubility parameters (as listed in anycomprehensive solvent information source such as the CRC Handbook ofPhysics and Chemistry) also assists in finding suitable solvent mixturesfor all three solutes. The identification of complex solvent mixturesfor different solutes is a well-known task in the formulation ofnumerous pharmaceutical and cosmetic products and can be readilyaccomplished by anyone skilled in the art.

Compositions in accordance with the present invention in which a PAIpeptide is the drug, poly(DTH adipate) is the tissue-compatible polymerand PEG is the second, phase-disrupting polymer, may be prepared bydissolving the PAI peptide and PEG in separate quantities of methanol,which solutions are then combined. The poly(DTH adipate) may then bedissolved in methylene chloride, with the methylene chloride solutionthen being combined with the methanol solution.

The solution of drug and polymer(s) is then precipitated into anon-solvent to form the sold single-phased dispersion of the drug in thetissue-compatible polymer, optionally including phase-separatedmicrodomains caused by the presence of the second phase-disruptingpolymer. The non-solvent should be miscible with the solvents which wereused to dissolve drug and polymer(s). Using a non-solvent for theprecipitation that is not fully miscible with each of the solvents usedto dissolve drug and polymers carries the danger of obtaining aseparation of the solvent mixture into two phases during theprecipitation process. Although this may be acceptable in somecircumstances, this is not the preferred mode of conducting theprecipitation step. For example, during early experiments, a homogeneoussolution of a peptide drug and a polymer was dissolved in a mixture ofmethanol and methylene chloride. When this homogeneous solvent mixturewas added into hexane used as the precipitation non-solvent, the solventmixture separated into two layers since methanol and hexane are notfully miscible in all proportions. This prevented the precipitation of asuitable single-phase drug-polymer matrix. Examples of suitablenon-solvents include ethers such as diethyl ether, diisopropyl ether,methyl t-butyl ether, and the like, as well as methyl ethyl ketone,acetone, ethyl acetate, acetonitrile, toluene, xylene, carbontetrachloride and the like. A copious excess of the non-solvent of atleast between 5-10 volumes compared to the volume of the dissolvingsolvents should be employed, and the non-solvent may be chilled as lowas the freezing point of the non-solvent to promote the coprecipitation.

The coprecipitated drug-polymer matrices are dried to remove anyresidual solvent and are then fabricated by known methods to produce avariety of useful articles. Depending on the thermal stability of thedrug and the polymer, the articles can be shaped by conventionalpolymer-forming techniques such as extrusion, compression molding,injection molding and the like to form implantable drug deliverydevices.

Poly(DTH adipate) films containing between trace amounts and 30 percentby weight of PAI peptides (as the drug) and between trace amounts andabout 30 percent by weight of PEG (as the phase-disrupting polymer) canbe inserted between an arterial stent and artery wall to prevent bloodclotting at the stent surface and the consequential arterial occlusion.The same composition can also be formed as a coating on the surface ofmedical devices and implants that come in contact with blood byconventional dipping or spray coating techniques to prevent theformation of blood clots on the device or implant surface. Implantabledrug delivery devices formed from the polymeric drug formulations of thepresent invention may otherwise be implanted in the body of a patient inneed thereof for site-specific drug delivery by procedures that areessentially conventional and well-known to those of ordinary skill inthe art.

In the management of thrombotic disorders the polymeric drugformulations of this invention may be utilized in a variety of shapedarticles. Subjects in need of treatment (typically mammalian) using thepolymeric drug formulations of this invention can be administered drugdosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompounds employed, the specific use for which these compounds areemployed, and other factors which those skilled in the medical arts willrecognize.

The polymeric drug formulations of this invention may be prepared forstorage under conditions suitable for the preservation of drug activityas well as maintaining the integrity of the polymers, and are typicallysuitable for storage at ambient or refrigerated temperatures.

The drug components to be incorporated in the polymeric drugformulations of this invention may be provided in a physiologicallyacceptable carrier, excipient, stabilizer etc., and may be provided insustained release or timed release formulation supplemental to thepolymeric formulation prepared in this invention. Acceptable carriers ordiluents for therapeutic use are well known in the pharmaceutical field,and are described, for example, in Remington's Pharmaceutical Sciences,Mack Publishing Co., (A. R. Gennaro edit. 1985). Such materials arenontoxic to the recipients at the dosages and concentrations employed,and include buffers such as phosphate, citrate, acetate and otherorganic acid salts, antioxidants such as ascorbic acid, low molecularweight (less than about ten residues) peptides such as polyarginine,proteins, such as serum albumin, gelatin, or immunoglobulins,hydrophilic polymers such as poly(vinylpyrrolidinone), amino acids suchas glycine, glutamic acid, aspartic acid, or arginine, monosaccharides,disaccharides, and other carbohydrates including cellulose or itsderivatives, glucose, mannose or dextrins, chelating agents such asEDTA, sugar alcohols such as mannitol or sorbitol, counterions such assodium and/or nonionic surfactants such as Tween, Pluronics orpolyethyleneglycol.

Dosage formulations of the compositions of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes, or by otherconventional methods such as irradiation or treatment with gases orheat. The pH of the compositions of this invention typically will bebetween 3 and 11, and more preferably from 5 to 9.

While the preferred route of administration for the cardiovascularapplications of the polymeric drug formulations of this invention is bysurgical implantation of a shaped article or film into a blood vessel,other methods of administration are also anticipated such assubcutaneously, intramuscularly, colonically, rectally, nasally orintraperitoneally, employing a variety of dosage forms such assuppositories, implanted pellets or small cylinders, aerosols, oraldosage formulations and topical formulations such as ointments, dropsand dermal patches.

The compounds of this invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles.

The polymeric drug formulations of this invention are suitable forapplications where localized drug delivery is desired, as well as insituations were a systemic delivery is desired.

The drugs incorporated into the formulations of this invention maydesirably further incorporate agents to facilitate their deliverysystemically to the desired drug target, as long as the delivery agentmeets the same eligibility criteria as the drugs described above. Theactive drugs to be delivered may in this fashion be incorporated withantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the drug molecules are coupled.

The polymeric drug formulations of this invention may be formed intoshaped articles, such as valves, stents, tubing, prostheses and thelike.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For thevarious suitable routes of administration, the absorption efficiencymust be individually determined for each drug by methods well known inpharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved. The release rate of the drug from the formulations of thisinvention are also varied within the routine skill in the art todetermine an advantageous profile, depending on the therapeuticconditions to be treated.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferablyfrom about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compoundsof this invention may be administered several times daily, and otherdosage regimens may also be useful.

In practicing the methods of this invention, the compounds of thisinvention may be used alone or in combination, or in combination withother therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this inventions may be coadministeredalong with other compounds typically prescribed for these cardiovascularconditions according to generally accepted medical practice, such asanticoagulant agents, thrombolytic agents, or other antithrombotics,including platelet aggregation inhibitors, tissue plasminogenactivators, urokinase, prourokinase, streptokinase, heparin, aspirin, orwarfarin. The compounds of this invention can be utilized in vivo,ordinarily in mammals such as primates, such as humans, sheep, horses,cattle, pigs, dogs, cats, rats and mice, or in vitro.

Certain preferred compounds of the present invention are characterizedby their ability to inhibit thrombus formation with acceptable effectson classical measures of coagulation parameters, platelets and plateletfunction, and acceptable levels of bleeding complications associatedwith their use. Conditions characterized by undesired thrombosis wouldinclude those involving the arterial and venous vasculature.

With respect to the coronary arterial vasculature, abnormal thrombusformation characterizes the rupture of an established atheroscleroticplaque which is the major cause of acute myocardial infarction andunstable angina, as well as also characterizing the occlusive coronarythrombus formation resulting from either thrombolytic therapy orpercutaneous transluminal coronary angioplasty (PTCA).

With respect to the venous vasculature, abnormal thrombus formationcharacterizes the condition observed in patients undergoing majorsurgery in the lower extremities or the abdominal area who often sufferfrom thrombus formation in the venous vasculature resulting in reducedblood flow to the affected extremity and a predisposition to pulmonaryembolism. Abnormal thrombus formation further characterizes disseminatedintravascular coagulopathy commonly occurs within both vascular systemsduring septic shock, certain viral infections and cancer, a conditionwherein there is rapid consumption of coagulation factors and systemiccoagulation which results in the formation of life-threatening thrombioccurring throughout the microvasculature leading to widespread organfailure.

Certain of the polymeric formulations of the present invention,incorporating cardiovascular drugs, prepared and used as disclosedherein, are believed to be useful for preventing or treating a conditioncharacterized by undesired thrombosis, such as (a) the treatment orprevention of any thrombotically mediated acute coronary syndromeincluding myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, (b) the treatment or prevention of anythrombotically mediated cerebrovascular syndrome including embolicstroke, thrombotic stroke or transient ischemic attacks, (c) thetreatment or prevention of any thrombotic syndrome occurring in thevenous system including deep venous thrombosis or pulmonary embolusoccurring either spontaneously or in the setting of malignancy, surgeryor trauma, (d) the treatment or prevention of any coagulopathy includingdisseminated intravascular coagulation (including the setting of septicshock or other infection, surgery, pregnancy, trauma or malignancy andwhether associated with multi-organ failure or not), thromboticthrombocytopenic purpura, thromboangitis obliterans, or thromboticdisease associated with heparin induced thrombocytopenia, (e) thetreatment or prevention of thrombotic complications associated withextracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypassor other oxygenation procedure, plasmapheresis), (f) the treatment orprevention of thrombotic complications associated with instrumentation(e.g. cardiac or other intravascular catheterization, intra-aorticballoon pump, coronary stent or cardiac valve), and (g) those involvedwith the fitting of prosthetic devices.

Anticoagulant therapy is also useful to prevent coagulation of storedwhole blood and to prevent coagulation in other biological samples fortesting or storage. Thus the polymeric cardiovascular drug formulationembodiments of this invention can be used in any environment in which itis desired that blood coagulation be inhibited, e.g., by incorporationinto material such as vascular grafts, stents, orthopedic prostheses,cardiac stents, valves and prostheses, extra corporeal circulationsystems and the like.

While many of the embodiments discussed above describe incorporation ofdrugs having cardiovascular effects, the invention is not so limited.Practically any therapeutic agent having water-solubility and othercharacteristics suitable for the practice of this invention, for avariety of therapeutic applications are acceptable.

The following non-limiting examples set forth herein below illustratecertain aspects of the invention. All parts and percentages are byweight unless otherwise noted and all temperatures are in degreesCelsius. The PAI peptide was obtained from COR Therapeutics of South SanFrancisco, Calif. Poly(DTH adipate) was prepared according to theprocedure provided in Example No. 2 of U.S. Pat. No. 5,216,115. PEG wasobtained from Aldrich Chemicals Milwaukee, Wis. The drug and polymerswere used without further purification. Solvents were of "HPLC grade"and were obtained from Fisher Scientific, Pittsburgh, Pa.

EXAMPLES

The following examples are divided into two sections. In the sectionlabeled as "Preferred Methods," the teachings disclosed in thisinvention are used to prepare release formulations with differentrelease rates. In the second section, labeled as "Comparative Examples,"methods known in the prior art are used to prepare similar releasedevices as those described in the first section. However, the releasedata obtained demonstrate that the methods known in the prior artprovided significantly less suitable release profiles.

PREFERRED METHODS

EXAMPLE 1 PREPARATION OF A PAI PEPTIDE CONTAINING RELEASE DEVICE WITH 10WEIGHT PERCENT LOADING OF PEG (M_(W) =1,000 da) AND 30 WEIGHT PERCENTLOADING OF PAI PEPTIDE USING THE MOST PREFERRED METHODS

PRECIPITATION

One of the above-listed PAI peptides (0.16 g) and PEG (0.057 g; M_(W)=1,000) were each dissolved in methanol (7.0 ml and 1.0 mlrespectively). Poly(DTH adipate) (0.32 g, M_(W) =110,000) was dissolvedin methylene chloride (7.0 ml). The peptide solution was pipetted intothe PEG solution, then this mixture was pipetted into the poly(DTHadipate) solution. The resulting homogeneous solution was then drippedinto stirred diethyl ether (140 ml) which was cooled by a dryice-acetone bath. A white flocculent precipitate was formed which wasisolated by careful filtration using a sintered glass funnel. Afterdrying under a high vacuum at ambient temperature, 0.43 g of white solidmaterial was recovered.

FILM FABRICATION

The completely dried PAI peptide-PEG-poly(DTH adipate) precipitate (0.43g) was carefully cut on a clean dry surface into small pieces andtransferred to a mold (4.0 cm×4.0 cm×0.1 mm, polished stainless steelsurface). No release substances were applied to the mold. The materialwas compression molded into a film of a thickness in the range of0.10-0.15 mm with the compression cycle shown in Table I. Upon removalfrom the mold, the film was translucent and pliable.

                  TABLE I    ______________________________________    COMPRESSION MOLDING FABRICATION    CYCLE FOR THE PREPARATION OF FILMS    CONSISTING OF PAI PEPTIDE-PEG-POLY(DTH ADIPATE)    TEMPERATURE (°C.)                  PRESSURE (psi)                               TIME (MINUTES)    ______________________________________    Ambient to 95°                   300         7    95°    6000         6    95-21° 6000         20    ______________________________________

TOTAL PAI PEPTIDE LOADING

Three pieces (total recorded weight of 5-6 mg) were cut from differentregions of PAI peptide loaded film and placed into a 10 ml volumetricflask. Tetrahydrofuran (0.5 ml) was added to dissolve the polymer and toliberate the entrapped PAI peptide. After the pieces of film hadcompletely disintegrated and a white solvent was evident, the volumetricflask was filled to the 10 ml level with phosphate buffer (9.5 ml) andgently agitated. An aliquot (1 ml) was pipetted from the flask, filtered(0.45 μm syringe filter), and analyzed for PAI peptide content by HPLC.The experimentally determined amount of PAI peptide found in the filmswas within ten percent of the theoretically expected amount.

PAI PEPTIDE IN-VITRO RELEASE

A device (9.97×15.6 mm, 55.1 mg) was cut from a PAI peptide-PEG-poly(DTHadipate) film, placed into a capped vial containing phosphate buffer (10ml, 37° C.), and incubated in a shaker bath. After 15 minutes, thedevice was transferred using forceps to another capped vial containingphosphate buffer (10 ml, 37° C.) and the device was further incubated inthe shaker bath. This process was repeated every 15 minutes for thefirst hour, every 30 minutes for the second hour, then hourly until fourhours. The device can be further incubated in phosphate buffer if longertime points are desired. Aliquots of the respective release media (1 ml)were removed from each vial, filtered, and the PAI peptide content wasassayed by HPLC analysis. The release profile is compiled in Table II.

                  TABLE II    ______________________________________    24-HOUR IN VITRO RELEASE PROFILE OF PAI PEPTIDE    FROM A DEVICE FORMULATED WITH 10 WEIGHT PERCENT OF    PEG (M.sub.w = 1,000 da) AND 30 WEIGHT PERCENT OF PAI PEPTIDE          Amt.     Cumul.              Release                                             Release    Time  Released Rel.          Cumul.                                       rate in                                             rate in    (min.)          (mg)     (mg)    % Rel.                                 % Rel.                                       mg/cm.sup.2                                             mg/cm.sup.2 min    ______________________________________    15    1.82     1.82    11.03 11.03 0.586 39.09    30    0.39     2.22    2.39  13.43 0.127 8.48    45    0.25     2.47    1.53  14.95 0.081 5.41    60    0.14     2.61    0.87  15.82 0.046 3.07    90    0.17     2.79    1.07  16.89 0.056 1.90    120   0.17     2.96    1.04  17.93 0.055 1.84    180   0.21     3.17    1.27  19.20 0.067 1.13    240   0.26     3.44    1.61  20.81 0.085 1.43    480   0.38     3.82    2.32  23.14 0.123 0.51    1440  0.77     4.59    4.65  27.78 0.247 0.26    ______________________________________

The translucent and foggy appearance of the film indicated thatphase-separated microdomains had formed. In this study, the targetedminimum release rate for PAI peptide was 0.2 micrograms/cm² min. Releaserates between 0.01 and 100 micrograms/cm² min are suitable for use inthe present invention. Release rates between 0.10 and 10 micrograms/cm²min are preferred. Table II illustrates that this formulation surpassedthe minimum release rate throughout the 24-hour release study. The bursteffect was significantly reduced compared to formulations preparedaccording to procedures known in the prior art.

EXAMPLE 2 PREPARATION OF A PAI PEPTIDE CONTAINING RELEASE DEVICE WITH 7WEIGHT PERCENT LOADING OF PEG (M_(W) =1,000 da) AND 30 WEIGHT PERCENTLOADING OF PAI PEPTIDE USING THE MOST PREFERRED METHODS.

PRECIPITATION

PAI peptide (0.4 g) and PEG (0.100 g; M_(W) =1,000) were each dissolvedin methanol (10.0 ml and 1.0 ml respectively). Poly(DTH adipate) (0.84g, M_(W) =110,000) was dissolved in methylene chloride (10.0 ml). ThePAI peptide solution was pipetted into the PEG solution, then thismixture was pipetted into the poly(DTH adipate) solution. The resultinghomogeneous solution was then dripped into stirred diethyl ether (150ml) which was cooled by a dry ice-acetone bath. A white flocculentprecipitate was formed which was isolated by careful filtration using asintered glass funnel. After drying under high vacuum at ambienttemperature 1.04 g of a white solid material was recovered.

FILM FABRICATION

The completely dried PAI peptide-PEG-poly(DTH adipate) precipitate (0.40g) was fabricated into a compression molded film as described in Example1, using the compression profile shown in Table I. Upon removal from themold, the film was translucent and pliable. Total PAI peptide loadingwas confirmed by HPLC analysis.

PAI PEPTIDE IN-VITRO RELEASE

A device (4.88×11.90 mm, 11.3 mg) was cut from a PAI peptide-PEG-poly(DTH adipate) film loaded with 30 weight percent PAI peptide and 7weight percent PEG. The release of PAI peptide was determined over a17-hour period as described in Example 1. The release data aresummarized in Table III.

                  TABLE III    ______________________________________    17-HOUR IN VITRO RELEASE PROFILE    OF PAI PEPTIDE FROM A DEVICE FORMULATED    WITH 7 WEIGHT PERCENT OF PEG (M.sub.w = 1,000 da)    AND 30 WEIGHT PERCENT OF PAI PEPTIDE          Amt.     Cumul.              Release                                             Release    Time  Released Rel.          Cumul.                                       rate in                                             rate in    (min.)          (mg)     (mg)    % Rel.                                 % Rel.                                       mg/cm.sup.2                                             mg/cm.sup.2 min    ______________________________________    15    0.17     0.17    5.08  5.08  0.14  9.55    30    0.04     0.21    1.29  6.37  0.04  2.42    60    0.09     0.30    2.72  9.09  0.07  2.55    300   0.12     0.42    3.74  12.83 0.10  0.44    1020  0.14     0.56    4.24  17.07 0.12  0.17    ______________________________________

Table III illustrates that the release rate for PAI peptide wassignificantly lower in this example than in Example 1. This is inaccordance with the teachings of this invention and illustrates that therelease rate decreases when the amount of second, phase-disruptingpolymer added into the formulation is reduced.

EXAMPLE 3 PREPARATION OF A PAI PEPTIDE CONTAINING RELEASE DEVICE WITH 14WEIGHT PERCENT LOADING OF PEG (M_(W) =1,000 da) AND 30 WEIGHT PERCENTLOADING OF PAI PEPTIDE USING THE MOST PREFERRED METHODS.

PRECIPITATION

PAI peptide (0.2 g) and PEG (0.097 g; M_(W) =1,000) were each dissolvedin methanol (7.0 ml and 1.0 ml respectively). Poly(DTH adipate) (0.37 g,M_(W) =110,000) was dissolved in methylene chloride (7.0 ml). The PAIpeptide solution was pipetted into the PEG solution, then this mixturewas pipetted into the poly(DTH adipate) solution. The resultinghomogeneous solution was then dripped into stirred diethyl ether (140ml) which was cooled by a dry ice-acetone bath. A white flocculentprecipitate was formed which was isolated by careful filtration using asintered glass funnel. After drying under high vacuum at ambienttemperature, 0.54 g of a white solid material was recovered.

FILM FABRICATION

The completely dried PAI peptide-PEG-poly(DTH adipate) precipitate (0.45g) was fabricated into a compression molded film as described in Example1, using the compression profile shown in Table I. Upon removal from themold, the film was translucent and pliable. Total PAI peptide loadingwas confirmed by HPLC analysis.

PAI PEPTIDE IN-VITRO RELEASE

A device (1.25×2.00 cm, 81.4 mg) was cut from an PAIpeptide-PEG-poly(DTH adipate) film loaded with 30 weight percent PAIpeptide and 14 weight percent PEG. The release of PAI peptide wasdetermined over a 2-hour period as described in Example I. The releasedata are summarized in Table IV.

                  TABLE IV    ______________________________________    2-HOUR IN VITRO RELEASE PROFILE OF PAI PEPTIDE    RELEASE FROM A DEVICE FORMULATED WITH 14    WEIGHT PERCENT OF PEG (M.sub.w = 1,000 da)    AND 30 WEIGHT PERCENT OF PAI PEPTIDE          Amt.     Cumul.              Release                                             Release    Time  Released Rel.          Cumul.                                       rate in                                             rate in    (min.)          (mg)     (mg)    % Rel.                                 % Rel.                                       mg/cm.sup.2                                             mg/cm.sup.2 min    ______________________________________    15    13.56    13.56   55.58 55.58 2.72  180.81    30    1.88     15.44   7.70  63.28 0.37  25.06    45    0.57     16.01   2.35  65.63 0.11  7.65    60    0.23     16.25   0.97  66.60 0.05  3.16    90    0.35     16.61   1.46  68.06 0.07  2.37    120   0.15     16.76   1.63  68.69 0.03  1.02    ______________________________________

Table IV illustrates that the release rate for PAI peptide wassignificantly increased in this example in comparison to Example 1. Thisis in accordance with the teachings of this invention and illustratesthat the release rate increases when the amount of second,phase-disrupting polymer added into the formulation is increased.

EXAMPLE IV PREPARATION OF A PAI PEPTIDE CONTAINING RELEASE DEVICECONTAINING A 30 WEIGHT PERCENT LOADING OF PAI PEPTIDE AND A 14 WEIGHTPERCENT LOADING OF PEG (M_(W) =20,000 da) USING THE MOST PREFERREDMETHODS.

PRECIPITATION

PAI peptide (0.2 g) and PEG (0.097 g; M_(W) =20,000 da) were eachdissolved in methanol (7.0 ml and 1.0 ml respectively). Poly(DTHadipate) (0.37 g, M_(W) =110,000) was dissolved in methylene chloride(7.0 ml). The PAI peptide solution was pipetted into the PEG solution,then this mixture was pipetted into the poly(DTH adipate) solution. Theresulting homogeneous solution was then dripped into stirred diethylether (140 ml) which was cooled by a dry ice-acetone bath. A whiteflocculent precipitate was formed which was isolated by carefulfiltration using a sintered glass funnel. After drying under high vacuumat ambient temperature 0.59 g of a white solid material was recovered.

FILM FABRICATION

The completely dried PAI peptide-PEG-poly(DTH adipate) precipitate (0.43g) was fabricated into a compression molded film as described in Example1, using the compression profile shown in Table I. Upon removal from themold, the film was translucent and pliable. Total PAI peptide loadingwas confirmed by HPLC analysis.

PAI PEPTIDE IN-VITRO RELEASE

A device (1.25×2.00 cm, 52.0 mg) was cut from a PAI peptide-PEG-poly(DTHadipate) film loaded with 30 weight percent PAI peptide and 14 weightpercent PEG (M_(W) =20,000). The release of PAI peptide was determinedover a 24-hour period as described in Example 1. The release data aresummarized in Table V.

                  TABLE V    ______________________________________    24-HOUR IN VITRO RELEASE PROFILE    OF PAI PEPTIDE FROM A DEVICE FORMULATED    WITH 14 WEIGHT PERCENT OF PEG (M.sub.w = 20,000 da) AND    30 WEIGHT PERCENT OF PAI PEPTIDE          Amt.     Cumul.              Release                                             Release    Time  Released Rel.          Cumul.                                       rate in                                             rate in    (min.)          (mg)     (mg)    % Rel.                                 % Rel.                                       mg/cm.sup.2                                             mg/cm.sup.2 min    ______________________________________     15   4.06     4.06    23.09 23.09 0.81  54.19     30   1.25     5.31    7.09  30.18 0.25  16.74     45   0.36     5.67    2.03  32.21 0.07  4.77     60   0.26     5.93    0.47  33.68 0.05  3.45     90   0.34     6.28    1.97  35.66 0.07  2.32    120   0.25     6.53    1.42  37.08 0.05  1.67    150   0.19     6.72    1.13  38.21 0.04  1.32    180   0.14     6.86    0.80  39.00 0.03  0.93    240   0.25     7.12    1.43  40.44 0.05  0.84    300   0.18     7.30    1.02  41.46 0.04  0.60    420   0.24     7.53    1.35  42.81 0.05  0.40    1440  0.53     8.06    3.01  45.82 0.10  0.10    ______________________________________

The device of this example is identical in all aspects to the devicedescribed in Example 3, except that the phase-disrupting polymer had ahigher molecular weight. Comparison of Table V with Table IV illustratesthe effect of the molecular weight of the phase-disrupting polymer onthe observed release rate. In this particular example, increasing themolecular weight of the phase-disrupting polymer resulted in a reductionof the initial burst and reduction in the overall release rate over a24-hour interval.

MASS BALANCE CONFIRMATION AFTER COMPLETION OF THE RELEASE PERIOD

After the 24-hour release study the amount of PAI peptide entrapped inthe film was released by first, removal of the device from the phosphatebuffer, then dissolving the device in tetrahydrofuran (2 ml) in a 10 mlvolumetric flask. After the film had completely disintegrated and awhite solid was evident, the volumetric flask was filled to the 10 mllevel with phosphate buffer (8.0 ml) and gently agitated. An aliquot (1ml) was pipetted from the flask, filtered (0.45 micron syringe filter),and analyzed for PAI peptide content by HPLC. The experimentallydetermined amount of PAI peptide found in the film was equivalent to theamount of PAI peptide expected to be entrapped in the film based on theamount released over the 24-hour test period. This result confirms theinternal consistency of the analytical methods used to measure andcalculate the release of PAI peptide from release devices.

EXAMPLE 5 PREPARATION OF A 24 WEIGHT PERCENT PAI PEPTIDE DEVICE WITHOUTPHASE-DISRUPTING POLYMER ADDED USING THE MOST PREFERRED METHODS

PRECIPITATION

PAI peptide (0.14 g) was dissolved in methanol (7.0 ml). Poly(DTHadipate) (0.421 g, M_(W) =110,000) was dissolved in methylene chloride(5.0 ml). The PAI peptide solution was pipetted into the poly(DTHadipate) solution. The resulting homogeneous solution was then drippedinto stirred diethyl ether (100 ml) which was cooled by a dryice-acetone bath. A white flocculent precipitate was formed which wasisolated by careful filtration using a sintered glass funnel. Afterdrying under high vacuum at ambient temperature, a white solid materialwas recovered.

FILM FABRICATION

The completely dried PAI peptide-poly(DTH adipate) precipitate (0.41 g)was fabricated into a compression molded film as described in Example 1,using the compression profile shown in Table I. Upon removal from themold, the film was transparent and pliable. Total PAI peptide loadingwas confirmed by HPLC analysis.

PAI PEPTIDE IN-VITRO RELEASE

A device (6.3×6.7 mm, 12.4 mg) was cut from a PAI peptide-poly(DTHadipate) film loaded with 25 weight percent PAI peptide. The release ofPAI peptide was determined over a 4-hour period as described inExample 1. The release data are summarized in Table VI.

                  TABLE VI    ______________________________________    4-HOUR IN VITRO RELEASE    PROFILE OF PAI PEPTIDE FROM A DEVICE    FORMULATED WITH 25 WEIGHT PERCENT OF PAI PEPTIDE          Amt.     Cumul.              Release                                             Release    Time  Released Rel.          Cumul.                                       rate in                                             rate in    (min.)          (mg)     (mg)    % Rel.                                 % Rel.                                       mg/cm.sup.2                                             mg/cm.sup.2 min    ______________________________________     30   0.007    0.007   0.21  0.21  0.008 0.26     60   0.004    0.011   0.13  0.34  0.004 0.15    120   0.001    0.012   0.03  0.37  0.001 0.02    240   0.001    0.013   0.04  0.41  0.001 0.01    ______________________________________

Table VI illustrates that essentially no PAI peptide release occurredover the four-hour test period. In a further study of the PAI peptiderelease from devices formulated without PEG, the release period wasextended to 30 days. It was found that less than 5 percent of the PAIpeptide loading was released over a 30-day period. This is unexpectedbased on teachings in the prior art, considering that PAI peptide is ahydrophilic, readily water-soluble drug. Based on prior art teachings, a30 weight percent loading of a water-soluble drug should have resultedin a significant burst effect followed by release of the drug.

COMPARATIVE EXAMPLES EXAMPLE 6 FORMULATION OF AN EVA RELEASE DEVICE AT APAI PEPTIDE LOADING OF 10 WEIGHT PERCENT ACCORDING TO THE PRIOR ARTMETHOD OF LANGER.

FILM FABRICATION

450 mg of EVA was dissolved in 20 ml of methylene chloride. Whilevigorously stirring the polymer solution, solid PAI peptide (50 mg whichhad previously been ground by mortar and pestle under dry conditions andsieved through a "270" mesh) was slowly added. A milky solution wasformed in which the drug was well dispersed. In an atmosphere ofnitrogen, the suspension was poured into a glass mold which had beenpre-cooled over a dry ice-acetone mixture. The circular glass mold wascovered with filter paper to facilitate the slow, overnight evaporationof the solvent. For further drying, the mold was kept under high vacuumfor four hours. Then the film was separated from the mold. To removeadditional traces of solvent trapped within the polymeric matrix, thefilm was placed between two tissue papers and kept under high vacuum atambient temperature for a minimum of three days.

PAI PEPTIDE IN-VITRO RELEASE

Samples were cut from the dry EVA-PAI peptide loaded films. The releaseof PAI peptide was determined over a four-hour period as described inExample 1. Films that were of the clinically useful thickness of0.10-0.20 mm were characterized by excessively strong initial bursts ofgreater than 90 percent of the loaded PAI peptide being released in thefirst 10 minutes. Such films are clearly unacceptable for thedevelopment of a clinically useful device formulation.

In this example, polyethylene-vinyl acetate copolymer (EVA) was used asa model polymer and film formulations were prepared as described in theseminal work of Langer (Siegel and Langer, J. Contrl. Rel., 14, 153-67(1990)). This is the method most commonly used in the prior art. Therelease profiles obtained with such films illustrate the difficultiesencountered when water-soluble drugs are incorporated into polymericfilms by the methods known in the prior art.

EXAMPLE 7 FORMULATION OF A RELEASE DEVICE AT A PAI PEPTIDE LOADING OF 20WEIGHT PERCENT ACCORDING TO THE PRIOR ART METHOD OF LANGER.

FILM FABRICATION

Poly(DTH sebacate) a member of the family of polyarylates! and 71 mg ofPAI peptide were used to prepare a suspension cast film of polymer anddrug as described for Example 6.

PAI PEPTIDE IN-VITRO RELEASE

Samples were cut from the dry poly(DTH sebacate)-PAI peptide loadedfilms. The release of PAI peptide was determined over a 30-day period asdescribed in Example 1.

The film samples obtained according to Example 7 released 84 percent ofthe total PAI peptide loading within three hours. The remaining 16percent of the drug loading were permanently entrapped within the filmand were not released even over a 30-day period. Such formulations areclearly inferior to the systems obtained according to the preferredmethods of this invention as illustrated in Examples 1 through 4.

The foregoing examples and description of the preferred embodimentshould be taken as illustrating, rather than as limiting, the presentinvention as defined by the claims. As will be readily appreciated,numerous variations and combinations of the features set forth above canbe utilized without departing from the present invention as set forth inthe claims. Such variations are not regarded as a departure from thespirit and scope of the invention, and all such modifications areintended to be included within the scope of the following claims.

What is claimed is:
 1. A polymeric drug formulation comprising asingle-phase dispersion of a water-soluble drug in a water-insolubletissue-compatible polymer matrix, and a water-soluble poly(alkyleneoxide) that is present in an amount effective to increase the releaserate of said water-soluble drug from said tissue-compatible polymermatrix.
 2. The polymeric drug formulation of claim 1, wherein saidtissue-compatible polymer is selected from the group consisting ofpoly(lactic acid), poly(glycolic acid), and copolymers thereof,poly(ethylene-co-vinyl acetate), poly(caprolactone), poly(orthoesters),poly(carbonates), poly(arylates), poly(imino-carbonates),poly(vinylpyrrolidone), pyran copolymer,poly(hydroxypropyl-methacrylamide-phenol),poly(hydroxy-ethyl-aspartamide-phenol), poly(ethyleneoxide)-poly(lysine) substituted with palmitoyl residues,poly(hydroxybutyric acid), poly(acetals), poly(dihydropyran),poly(cyanoacrylates) and cross-linked and amphipathic block copolymersof hydrogels.
 3. The polymeric drug formulation of claim 2, wherein saidtissue-compatible polymer is a poly(arylate).
 4. The polymeric drugformulation of claim 3, wherein said polyarylate ispoly(desaminotyrosyl-tyrosine hexyl ester adipate).
 5. The polymericdrug formulation of claim 1, wherein said water-soluble drug is anon-peptide drug selected from the group consisting of antibiotics,cytotoxic agents and oligonucleotides.
 6. The polymeric drug formulationof claim 1, wherein said water-soluble drug is a peptide drug selectedfrom the group consisting of immunoglobulins, immunoglobulin fragmentsand platelet aggregation inhibiting peptides.
 7. The polymeric drugformulation of claim 6, wherein said peptide drug is a plateletaggregation inhibiting peptide.
 8. The polymeric drug formulation ofclaim 1, containing a drug loading up to about 50 percent by weight. 9.The polymeric drug formulation of claim 8, containing a drug loading upto about 30 percent by weight.
 10. The polymeric drug formulation ofclaim 9, containing a drug loading between about 10 and about 20 percentby weight.
 11. The polymeric drug formulation of claim 1, wherein saidwater-soluble poly(alkylene oxide) is poly(ethylene glycol).
 12. Thepolymeric drug formulation of claim 1, wherein said water-solublepoly(alkylene oxide) is present at a level between about 2 and about 30percent by weight.
 13. A blood-contacting device or implant coated witha polymeric drug formulation comprising a single-phase dispersion of aplatelet aggregation inhibiting peptide in a water-insolubletissue-compatible polymer matrix and a water-soluble poly(alkyleneoxide) that is present in an amount effective to increase the releaserate of said peptide from said tissue-compatible polymer matrix.